Medical dispensing containers made of glass or polymeric materials, the walls of which are non-collapsible, typically require an air inlet when a medical fluid is withdrawn therefrom, to prevent the formation of vacuum therein. Typically, vials containing a medical fluid are closed by rubber stoppers which are pierced by a spike of a transfer device having a duct for the passage of the medical fluid and a ventilation duct. Examples of devices comprising a liquid fluid duct and a ventilation duct are disclosed, for instance, in U.S. Pat. No. 3,797,521, U.S. Pat. No. 4,262,671, U.S. Pat. No. 4,623,343, U.S. Pat. No. 4,857,068, U.S. Pat. No. 5,041,106, and U.S. Pat. No. 6,139,534.
The present invention is particularly concerned with the liquid transfer into a container containing a medicament reconstitutable upon addition of said liquid, and the subsequent removal of the reconstituted medicament from said container. More particularly, the device of the invention is suitable for the preparation and dispensing of some diagnostic or therapeutic agents, such as those comprising a gaseous component including, for instance, gas-filled microvesicles for ultrasound diagnostic and/or therapeutic use.
Gas-filled microvesicles for ultrasound diagnostic and/or therapeutic use include suspensions of gas bubbles having a diameter of a few microns dispersed in an aqueous medium. Of particular interest are gas bubbles which are stabilized by means of suitable additives such as, for example emulsifiers, oils, thickeners or sugars, or by entrapping or encapsulating the gas or a precursor thereof in a variety of systems. These agents are designed to be used primarily as intravenous or intra-arterial injectables in conjunction with the use of medical echographic equipment which employs for example, B-mode image formation (based on the spatial distribution of backscatter tissue properties) or Doppler signal processing (based on Continuous Wave or pulsed Doppler processing of ultrasonic echoes to determine blood or liquid flow parameters).
A first category of stabilized bubbles or microvesicles is generally referred to in the art as “microbubbles” and includes aqueous suspensions in which the bubbles of gas are bounded at the gas/liquid interface by a very thin envelope (film) involving a stabilizing amphiphilic material disposed at the gas to liquid interface. Microbubble suspensions are typically prepared by contacting powdered amphiphilic materials, e.g. freeze-dried preformed liposomes or freeze-dried or spray-dried phospholipid solutions, with air or other gas and then with an aqueous carrier, while agitating to generate a microbubble suspension which can then be administered.
Examples of aqueous suspension of gas microbubbles and preparation thereof are disclosed, for instance, in U.S. Pat. No. 5,271,928, U.S. Pat. No. 5,445,813, U.S. Pat. No. 5,413,774, U.S. Pat. Nos. 5,556,610, 5,597,549, U.S. Pat. No. 5,827,504, WO 97/29783 and WO 04/069284.
Commercially available ultrasound contrast agents of this type include for instance SonoVue® (Bracco International BV).
A second category of microvesicles is generally referred to in the art as “microballoons” or “microcapsules” and includes suspensions in which the bubbles of gas are surrounded by a solid material envelope of a lipid or of natural or synthetic polymers. Examples of microballoons and of the preparation thereof are disclosed, for instance, in U.S. Pat. No. 5,711,933 and U.S. Pat. No. 6,333,021.
Whilst the above formulations are administered as suspensions of gas-filled microvesicles in a suitable physiologically acceptable liquid, for storage purposes it is in general preferred to use precursors of said microvesicles in dry (e.g. lyophilized) form, as disclosed in the above mentioned patents and patent applications. The microvesicles suspension is then obtained by adding to said dry precursors, in the presence of a suitable gas (e.g a fluorinated gas), a physiologically acceptable liquid carrier, preferably under agitation. The dry precursor can for instance be stored in a vial (e.g. of glass) in the presence of a desired gas, said vial being sealed with a suitable stopper (e.g. of rubber), through which the liquid carrier can be injected. The contrast agent formulation can thus be supplied in a kit comprising a vial (containing the dry precursor and the gas) and a pre-filled syringe (containing the physiologically acceptable liquid carrier). The syringe can be associated with a suitable liquid transfer device which typically comprises a spike for piercing the stopper, a first conduit for injecting the liquid carrier into the vial and withdrawing the formed microbubbles suspension from it, and a second conduit (vent tube) for allowing a gas/air flow from and into the container during the respective liquid injection and withdrawal phases. Examples of such devices are disclosed, for instance, in U.S. Pat. No. 6,743,214.
When the suspension of gas-filled microbubbles has been reconstituted with the addition of the liquid, it may however be desirable to keep said reconstituted suspension in the vial for a relatively long time (e.g. few hours) before using. As observed by the Applicant, such a relatively long storage time of the reconstituted suspension may however pose some problems, particularly in connection with a possible exchange between the gas contained inside the container and the outer atmosphere air. This may be for instance the case when a liquid transfer device (such as the one disclosed in U.S. Pat. No. 6,743,214) is employed, where a direct fluid-gas passage is present between the inside of the container and the outer ambient, with consequent possible air inlet inside the container. While it has been demonstrated that a fluorinated gases employed for filling the microvesicles can be admixed with relatively high amounts of air (e.g. up to 70-80% by volume of air) without substantially modifying the properties and stability of the gas-filled microvesicles (as described for instance in EP patent no. 682 530), an excessive amount of air may nevertheless negatively affect said properties and stability. In addition, when the gas filled microvesicles already contain a mixture of fluorinated gas and air (as in the above mentioned EP 682 530), the negative effects deriving by said air inlet may be more evident.
Furthermore, the above undesirable gas/air exchange may similarly take place also when the transfer device is connected to the vial and left in place for a certain time, without connecting a syringe thereto and/or injecting a liquid into the vial.
In co-pending International patent application PCT/EP2005/056975, the Applicant suggests to insert a suitable valve in the vent tube of the transfer device, so to substantially avoid said gaseous exchange under steady state conditions.